The 13-story hotel was built in 1912-13 by German-born stockbroker Gustavus Sidenberg (1843–1915), whose wife the hotel is named after,[3] and was designed by the firm of George & Edward Blum, who specialized in designing apartment buildings. The hotel, which was known in its heyday as "the Waldorf of Harlem", exemplifies the Blums' inventive use of terra-cotta for ornamentation, and has been called "one of the most visually striking structures in northern Manhattan."[2]

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The 13-story[4] hotel – with its striking white terra cotta facade with ornamentation made specifically for the project and not pre-fabricated stock items, as was standard practice[2] – opened in 1913 and was, until the construction of the Adam Clayton Powell Jr. State Office Building across the street in 1973, the tallest building in Harlem. It was primarily an apartment hotel, but also accepted temporary guest as well.[2] In its early years the hotel accepted only white guests, but it was bought in 1937 by Love B. Woods, an African American businessman, who in 1940 ended its racial segregation policy.[3][4]

The hotel had a two-story penthouse dining room which features views of Long Island Sound to the east and the Palisades to the west,[4] as well as a bar and grill. In the 1940s and 1950s, the Theresa became a center of the social life of the black community of Harlem; it was then that it was known as "the Waldorf of Harlem." The hotel profited from the refusal of prestigious hotels elsewhere in the city to accept black guests. As a result, black businessmen, performers, and athletes were thrown under the same roof. The building was also the location of such institutions as A. Phillip Randolph's March on Washington Movement, the March Community Bookstore, and the Organization of Afro-American Unity created by Malcolm X[2] after he left the Nation of Islam.

The hotel suffered from the continued deterioration of Harlem through the 1950s and 1960s, and, ironically, from the end of segregation elsewhere in the city. As African Americans of means now had alternatives, they stopped coming to Harlem. The owners had not upgraded or modernized the hotel in decades, and it was said to be "dowdy" at best.[2]

New owners began converting the building to office space beginning in 1966,[2] and the hotel closed in 1967. The building was renovated and restored, with the exterior largely kept as it had originally been, instead of being replaced with an aluminum and glass facade, an alternative which had been considered.[2] The building reopened in 1970[2] as Theresa Towers, though a sign with the old name is still painted on the side of the building, and the old name is still commonly used. As well as housing commercial and professional tenants, it serves as an auxiliary campus for Columbia University's Teachers College and the Touro College of Pharmacy.